The pathophysiology of orthostatic intolerance including orthostatic hypotension (OH) is poorly understood and hence its treatment has been unsatisfactory. The focus of this proposal is on the elucidation of mechanisms of orthostatic intolerance in the postural tachycardia syndrome (POTS) and neurogenic OH and develop pathophysiologically- based new treatment strategies. We will undertake a double-blind, randomized, 4-way cross-over study of pyridostigmine in the treatment of neurogenic OH. This strategy of acetylcholinesterase inhibition to increase the safety factor of ganglionic transmission could improve OH without supine hypertension. A similar study will evaluate its efficacy in neurogenic POTS, where denervation is often also present. A blinded study will evaluate if sodium chloride will increase plasma volume and if urinary sodium secretion is a reliable surrogate measure of plasma volume. Seven studies will evaluate the pathophysiology of POTS. One is a power spectral analysis of autonomic rhythms that modulate the EEG. In particular, an ultra-low frequency band (0.02-0.05 Hz) is reduced in POTS and may be of brainstem origin. One study will evaluate if carbonic anhydrase inhibition will improve cerebral perfusion and symptoms of POTS, since hypocapnia on head-up tilt is present. Two studies are focused on the venous capacitance bed in the legs and abdomen. One evaluates if the capillaries are excessively leaky, using plethysomographic techniques. The other evaluates, using a modified G- suit (compresses specific venous compartments), which capacitance beds are most responsible for orthostatic intolerance. Techniques are now available to study the systemic )beat-to-beat BP and impedance methodology), mesenteric (superior mesenteric blood flow ultrasonography), cerebrovascular (transcranial doppler) circulations simultaneously, and sympathetic discharges can be directly measured using microneurography. The hypothesis that pre-ganglionic lesions cause a different pattern of autonomic vascular involvement to post- ganglionic lesions will be tested. Finally, the independent predictors of auto-regulatory adaptation of the cerebrovascular circulation in neurogenic OH will be studied.